One of the strongest clinical associations with autoantibodies directed to components of the Ro/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. Based on extensive data collection from the U.S. Research Registry for Neonatal Lupus, the risk of CHB is 10-fold higher in subsequent pregnancies of women who have had a previously affected child. Despite the attempt of large multicenter studies to forestall disease by serial in utero monitoring, irreversibe block and extensive myocardial injury have been documented within 7 days of a normal rhythm and PR interval. CHB is associated with a substantial mortality and morbidity. To date no preventative therapies have been successfully developed and complete block has never been reversed. Two recent prospective studies (20 mothers from U.S. and 15 from Europe) utilizing an identical protocol of IVIG at replacement doses demonstrated 1) this intervention does not prevent the recurrence of CHB 2) the recurrence rate of 17-18% is robust 3) recruitment of patients is feasible. During the time period of the IVIG trials, basic science exploring the pathogenesis of disease supported the notion that Toll Like Receptor (TLR) signaling following ligation of ssRNA (hY3) complexed to the Ro60 protein contributes to fibrosis. This observation led to in vitro studies addressing inhibition of endosomal acidification by chloroquine. Subsequent translation to patients was approached by evaluating hydroxychloroquine (HCQ) use in an extensive case control study restricted to lupus mothers and a separate retrospective evaluation of whether HCQ reduces the expected recurrence rate of CHB. The combined data suggest efficacy. Accordingly, the specific aim of this study is to determine whether HCQ prevents the recurrence of CHB. This will be approached in a Phase II trial of pregnant women with anti-Ro antibodies who have had a previous child with CHB. This is designed as an open-label trial employing Simon's 2-stage optimal design to allow for early stopping due to absence of efficacy. The first stage requires 19 subjects, which are expected to be enrolled with all pregnancies completed within two years. Serial echocardiograms (monitor PR interval) and evaluation of maternal and cord blood biomarkers (HCQ levels, IFNa signatures, and Ab titers) will be part of the protocol to address maternal compliance, pathobiology and efficacy. If 3 mothers have a child with 2nd or 3rd degree CHB, the study is terminated after the first stage. If < 3 recurrences are observed, the 2nd stage will be launched as part of a full scale RO1 application with an additional 35 subjects enrolled. The study governance will be at NYU and the IRB has approved the protocol at this site. An IND has been issued by the FDA. Ultimately, HCQ will be considered efficacious for CHB prevention if < 6 cases occur among 54 subjects. While it is acknowledged that a prospective randomized control study would be most robust, the rarity of disease may be limiting. However, data on women refusing drug will be equivalently maintained. A positive result will likely change the management of all anti-Ro positive women who have had a previous child with CHB. Furthermore, potential prevention would justify screening of all pregnant women for anti-Ro antibodies.